This supplement/revision is in response to the FOA entitled "NIAID Competing Supplements for B cell Immunology and HIV-neutralizing Antibody Projects." The experiments proposed will apply a recent conceptual advance in B cell biology to the problem of eliciting broadly neutralizing antibodies against HIV-1. The TNF family member, B-Lymphocyte Stimulator (BLyS), plays a critical role in B cell homeostasis and selection. Recent results show that the proportion of newly formed B cells surviving transitional selection can be modulated based on BLyS availability, thus varying the stringency of selection at this checkpoint. We therefore hypothesize that raising BLyS levels will relax selective stringency, affording the maturation of clonotypes otherwise lost at this checkpoint. We further hypothesize that this expansion will increase the likelihood of eliciting broadly neutralizing antibodies against HIV envelope proteins. The studies proposed herein will test this idea by determining whether a brief period of BLyS pre-treatment affords broadly neutralizing primary and secondary humoral responses to immunization with native HIV-1 gp120. We will treat mice for 10 days with BLyS, followed by primary and booster immunizations with HIV-1 gp120. The resulting antisera will be assessed for broadly neutralizing activity in vitro using a well-established virus pseudotype assay. [unreadable] [unreadable] [unreadable]